Nasal delivery of apomorphine

ABSTRACT

Intranasal delivery methods and compositions for the delivery of dopamine receptor agonists are provided which are effective for the amelioration of erectile dysfunction in a mammal without causing substantial intolerable adverse side effects to the mammal. Nasally administered compositions for treating male erectile dysfunction in a mammal are also provided which include a therapeutically effective amount of a dopamine receptor agonist which has been dispersed in a system to improve its solubility and/or stability.

CROSS REFERENCES TO RELATED APPLICATIONS

This application is a Continuation of U.S. application Ser. No.09/334,304 now U.S. Pat. No. 6,436,950 B1, issued Aug. 20, 2002, filedJun. 16, 1999, which claims the benefit of U.S. Provisional ApplicationNo. 60/096,545, filed Aug. 14, 1998.

BACKGROUND OF THE INVENTION

The present invention relates generally to intranasal delivery methodsand dosage forms. More particularly, methods and dosage forms for thesafe and reliable intranasal delivery of apomorphine to ameliorateerectile dysfunction in a mammal are provided.

Apomorphine is a potent dopamine receptor agonist which has a variety ofuses. For example, it has been effectively used as an adjunctivemedication in the treatment of Parkinson's disease which is complicatedby motor fluctuations (T. van Laar et al., Arch. Neurol., 49: 482-484(1992)). In particular, apomorphine has been used for relieving“off-period” symptoms in Parkinson patients with such responsefluctuations. In the study by van Laar et al., the intranasally appliedapomorphine used to achieve the results reportedly included an aqueoussolution of apomorphine hydrochloride (HCL) at a concentration of 10mg/ml. This formulation is also used for parenteral application and ispublished in different Pharmacopeia's.

Also, U.S. Pat. No. 5,756,483 issued to Merkus (hereinafter “the '483patent”) which is hereby incorporated by reference, discloses theintranasal delivery of a variety of compositions, including apomorphinein combination with a cyclodextrin and/or a polysaccharide and/or asugar alcohol for treating Parkinson's disease. The '483 patent,however, discloses very narrow dosage ranges of 0.1 to 2 mg ofapomorphine per nostril which is specifically tailored for theamelioration of the “off-period” symptoms of Parkinson's disease.

Further, U.S. Pat. No. 5,770,606 issued to El-Rashidy et al.(hereinafter “the '606 patent”), which is hereby incorporated byreference, discloses the delivery of apomorphine in a sublingual dosageunit for alleviating psychogenic impotence or erectile dysfunction withno substantial undesirable side effects. The '606 patent furtherincludes results from a study conducted by the inventors on the effectof apomorphine delivered intranasally on erectile dysfunction. The studysuggested that intranasal delivery of apomorphine at concentrations of2.5 mg to 3.5 mg was effective for eliciting an erection in patientssuffering from erectile dysfunction, however, since the studyparticipants suffered extensive and serious side effects includinghypotension, nausea, vomiting, impaired vision, diaphoresis and ashencoloring, it was concluded that intranasal delivery of apomorphine totreat erectile dysfunction was insufficiently safe and reliable to be aviable commercial product.

Accordingly, it is one of the purposes of this invention, among others,to provide a safe and reliable intranasal delivery system forapomorphine that ensures delivery of therapeutic amounts of the druginto the bloodstream which is fast acting, easily administered andcauses no substantial adverse side effects.

SUMMARY OF THE INVENTION

It has now been discovered that this and other purposes can be achievedby the present invention, which provides for a method for amelioratingmale erectile dysfunction in a mammal. This method includes the nasaladministration of a dopamine receptor agonist to the mammal before,during or after sexual activity in an amount sufficient to induce anerection without inducing substantial intolerable side effects in themammal. Preferably, the dopamine receptor agonist is apomorphine.

The present invention also provides for a pharmaceutical composition fortreating male erectile dysfunction in a mammal without causingsubstantial intolerable adverse side effects that includes atherapeutically effective amount of a dopamine receptor agonist incombination with a nasal delivery system. Preferably, the dopaminereceptor agonist is selected from the group consisting of apomorphine,chemically modified equivalents and pharmaceutical salts thereof andeven further preferably, the dopamine receptor agonist is apomorphine.The chemically modified equivalents of apomorphine preferably include apro-drug. Further, it is preferable that apomorphine is dispersed in anaqueous or non-aqueous formulation.

In addition, the nasal delivery system of the pharmaceutical compositioncan include a buffer to maintain the pH of the dopamine receptoragonist, a pharmaceutically acceptable thickening agent and a humectant.The pharmaceutical composition can further include one or morepharmaceutical excipients and even further include a pharmaceuticallyacceptable preservative.

The buffer of the nasal delivery system can be selected from the groupincluding acetate, citrate, prolamine, carbonate and phosphate buffers.

The thickening agent of the nasal delivery system can be selected fromthe group including methyl cellulose, xanthan gum, carboxymethylcellulose, hydroxypropyl cellulose, carbomer, polyvinyl alcohol,alginates, acacia, chitosans and combinations thereof.

The humectant of the nasal delivery system can be selected from thegroup including sorbitol, glycerol, mineral oil, vegetable oil andcombinations thereof.

The present invention also provides a method of treating erectiledysfunction in a male mammal including nasally administering apharmaceutical composition including a therapeutically effective amountof a dopamine receptor agonist in combination with a nasal deliverysystem wherein the pharmaceutical composition does not cause substantialintolerable adverse side effects in the mammal.

The present invention also provides for a nasally administeredpharmaceutical composition that includes a therapeutically effectiveamount of a dopamine receptor agonist dispersed in a buffer to maintainits pH, a pharmaceutically acceptable thickening agent and a humectant,wherein said nasally administered pharmaceutical composition does notcause substantial intolerable adverse side effects when administered toa mammal. The dopamine receptor agonist of the nasally administeredpharmaceutical composition is selected from the group includingapomorphine, chemically modified equivalents and pharmaceutical saltsthereof. It is further preferable that chemically modified equivalentsof apomorphine include a pro-drug.

The present invention also provides for a method of treating impotenceand male erectile dysfunction in a human in need of such treatmentincluding administering to a nasal membrane of the human an effectiveamount of a nasally administered pharmaceutical composition including atherapeutically effective amount of a dopamine receptor agonistdispersed in a buffer to maintain its pH, a pharmaceutically acceptablethickening agent and a humectant, wherein the nasally administeredpharmaceutical composition does not cause substantial intolerableadverse side effects when administered to the human.

Another preferred method of the present invention also provides fortreating male erectile dysfunction in a mammal without causingsubstantial intolerable adverse side effects. This method includesadministering into a nasal cavity of the mammal a therapeuticallyeffective dosage of a dopamine receptor agonist in combination with anasal delivery system. The nasal delivery system includes apharmaceutically acceptable buffer, a thickening agent and a humectant.The dopamine receptor agonist is selected from the group includingapomorphine, chemically modified equivalents and pharmaceutical saltsthereof Preferably, chemically modified equivalents of apomorphineinclude a pro-drug.

Another preferred method of the present invention is a method foradministering a therapeutically effective amount of a dopamine receptoragonist to a mammal through a nasal membrane without causing substantialintolerable adverse side effects. This method includes delivering to thenasal membrane of a mammal a dopamine receptor agonist dispersed in anasal delivery system which includes a pharmaceutically acceptablebuffer, a thickening agent and a humectant. Preferably, the dopaminereceptor agonist is effective for the treatment of male erectiledysfunction in a mammal.

The present invention also provides for an intranasal dosage unit fortreating impotency or erectile dysfunction in a mammal which does notcause substantial intolerable adverse side effects. The dosage unitincludes an effective amount of a dopamine receptor agonist incombination with an intranasal carrier. The intranasal carrier includesa buffer. The buffer pH is selected to enhance absorption of thedopamine receptor agonist and to produce an erection within about 60minutes of administering the dosage unit to a nasal mucosa of themammal. Preferably, an erection is produced within about 45 minutes,more preferably within about 30 minutes, most preferably within about 15minutes, and even further preferably in less than about 15 minutes.

The intranasal carrier of the intranasal dosage unit is preferably anaqueous solution. Further, the aqueous solution can be selected from thegroup including aqueous gels, aqueous suspensions, aqueous liposomaldispersions, aqueous emulsions, aqueous microemulsions and combinationsthereof.

Alternatively, the intranasal carrier of the intranasal dosage unit is anon-aqueous solution. The non-aqueous solution can be selected from agroup including non-aqueous gels, non-aqueous suspensions, non-aqueousliposomal dispersions, non-aqueous emulsions and non-aqueousmicroemulsions and combinations thereof.

The intranasal carrier of the intranasal dosage unit can also be acombination of an aqueous solution and a non-aqueous solution.

Alternatively, the carrier of the intranasal dosage unit is a powderformulation. The powder formulation can be selected from a groupincluding simple powder mixtures, powder microspheres, coated powdermicrospheres, liposomal dispersions and combinations thereof.Preferably, the powder formulation is powder microspheres. The powdermicrospheres are preferably formed from various polysaccharides andcelluloses selected from the group including starch, methylcellulose,xanthan gum, carboxymethylcellulose, hydroxypropyl cellulose, carbomer,alginate polyvinyl alcohol, acacia, chitosans and combinations thereof.

The intranasal dosage unit can also include an excipient havingbio-adhesive properties. Preferably, the buffer of the intranasal dosageunit is selected to have a pH of from about 3 to about 10 and morepreferably from about 3.5 to 7.0.

Preferably, the intranasal dosage unit includes a humectant. A humectantcan be selected from the group consisting of soothing agents, membraneconditioners, sweeteners and combinations thereof.

The present invention also provides for a nasally administeredpharmaceutical composition for treating male erectile dysfunction in amammal including a therapeutically effective amount of a dopaminereceptor agonist which has been dispersed in a system to improve itssolubility. The dopamine receptor agonist of this composition isselected from the group consisting of apomorphine, chemically modifiedequivalents and pharmaceutical salts thereof. The system of thiscomposition includes one of the following or combinations thereof: aglycol derivative; a sugar alcohol; glycerin; propylene glycol andglycerin; polyethylene glycol 400; ascorbic acid and water; sodiumascorbate and water; or sodium metabisulfite and water. Preferred glycolderivatives include propylene glycol and polyethylene glycol. Preferredsugar alcohols include mannitol and xylitol.

The present invention also provides for a nasally administeredpharmaceutical composition for treating male erectile dysfunction in amammal including a therapeutically effective amount of a dopaminereceptor agonist which has been dispersed in a system to improve itsstability. The dopamine receptor agonist of this composition is selectedfrom the group consisting of apomorphine, chemically modifiedequivalents and pharmaceutical salts thereof. The system of thiscomposition includes one of the following or combinations thereof: aglycol derivative; a sugar alcohol; glycerin; propylene glycol andglycerin; polyethylene glycol 400; ascorbic acid and water; sodiumascorbate and water; or sodium metabisulfite and water. Preferred glycolderivatives include propylene glycol and polyethylene glycol. Preferredsugar alcohols include mannitol and xylitol.

These and other advantages of the present invention will be appreciatedfrom the detailed description and examples which are set forth herein.The detailed description and examples enhance the understanding of theinvention, but are not intended to limit the scope of the invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to compositions and methods fortreating sexual dysfunction in a mammal. In particular, a method isprovided for ameliorating male erectile dysfunction in a mammal bynasally administering to the mammal a therapeutically effective amountof a dopamine receptor agonist before, during or after sexual activitywhich is sufficient to induce an erection without causing substantialadverse side effects in the mammal.

For purposes of the present invention, the phrase “erectile dysfunction”is intended to encompass certain medically related symptoms resulting inthe inability of a male to perform sexually, including peniledysfunction, as well as male impotence. As used herein, the term“impotence” is intended to mean the inability of a male to achieveand/or sustain a penile erection sufficient for vaginal penetration andintercourse.

As used herein, a “dopamine receptor agonist” is intended to encompassthose members of the dopamine receptor agonist family which are able toameliorate male erectile dysfunction when administered to a mammal.Apomorphine is an example of such a composition. Thus, the presentinvention is intended to encompass apomorphine and its functionalequivalents including pharmaceutical salts and chemically modifiedequivalents thereof, including for example pro-drug forms ofapomorphine. Apomorphine can be represented by the formula:

and in the present invention can exist in a free base form or as an acidaddition salt. For the purposes of the present invention, apomorphinehydrochloride is preferred; however, other pharmacologically acceptablemoieties thereof can be utilized as well. The term “apomorphine” as usedherein includes the free base form of this compound as well aspharmacologically acceptable acid addition salts thereof. In addition tothe hydrochloride salt of apomorphine, other pharmacologicallyacceptable acid addition salts of apomorphine include the hydrobromide,the hydroiodide, the bisulfate, the phosphate, the acid phosphate, etc.

For the purposes of the present invention, apomorphine or a similarlyacting dopamine receptor agonist is administered nasally in an amountsufficient to excite cells in the mid-brain region of the patient butwithout substantial adverse side effects.

This cell excitation is believed to be part of a cascade of stimulationthat is likely to include neurotransmission with serotonin and oxytocin.Because dopamine receptors agonists act-directly on regions of themid-brain, the present invention also contemplates the use of suchagonists for improving the sexual desire in both male and femalemammals, as well as the amelioration of erectile dysfunction in males asset forth above.

The dopamine receptors in the mid-brain region of a patient can bestimulated to a degree sufficient to cause an erection by the nasaladministration of apomorphine so as to maintain an adequate plasmaconcentration of apomorphine. The amount of apomorphine nasallyadministered is an amount sufficient to cause an erection but is lowenough not to cause substantial intolerable adverse side effects. Asused herein, “substantial intolerable adverse side effects” includethose effects caused by either the delivery system or the dopaminereceptor agonist which are incompatible with the health of the user orwhich are so unpleasant as to discourage the continued use of thecomposition. Such effects include, for example, hypotension, nausea,vomiting, impaired vision, diaphoresis and ashen coloring.

Apomorphine is nasally administered about 30 to about 45 minutes priorto sexual activity, preferably about 15 to about 20 minutes prior tosexual activity, and more preferably less than 15 minutes prior tosexual activity.

The compositions according to the present invention can be administered,for example, as a nasal spray, nasal drop, suspension, gel, ointment,cream or powder. The administration of a composition can also includeusing a nasal tampon or a nasal sponge containing a composition of thepresent invention.

The dopamine receptor agonist can also be brought into a viscous basisvia systems conventionally used, for example, natural gums,methylcellulose and derivatives, acrylic polymers (carbopol) and vinylpolymers (polyvinylpyrrolidone). In the present compositions, many otherexcipients known in the art can be added such as preservatives,surfactants, co-solvents, adhesives, antioxidants, buffers, viscosityenhancing agents and agents to adjust the pH and the osmolarity.

The amount of dopamine receptor agonist administered to a patient willvary according to the delivery system used, and the age and weight ofthe patient. There are two critical parameters for selecting theappropriate dosage levels of the dopamine receptor agonist. First, thedosage level must be effective for achieving an erection in the patientand second, the dosage level must not cause substantial intolerableadverse side effects to the patient.

The onset of substantial intolerable adverse side effects, for example,nausea and/or vomiting, can be obviated or delayed by nasally deliveringa dopamine receptor agonist at a controlled dissolution rate so as toprovide circulating serum levels and mid-brain tissue levels of thedopamine receptor agonist sufficient for an erection and withoutinducing nausea and/or vomiting. When it is necessary to administerhigher doses of a dopamine receptor agonist, for example, doses aboveabout 2 mg, the likelihood of a substantial intolerable adverse sideeffect onset can be reduced by concurrently administering a ganglionicagent capable of inhibiting the ganglionic response, for example,nicotine or lobeline sulfate.

Other antiemetic agents that can be used in accordance with the presentinvention include metoclopramide; phenothiazines such as chlorpromazine,prochlorperazine, pipamazine, thiethylperazine and oxypendylhydrochloride; serotonin (5-hydroxytryptamine or 5-IIT) agonists such asdomperidone, odansetron and histamine antagonists including buclizinehydrochloride, cyclizine hydrochloride and dimenhydrinate;parasympathetic depressants such as scopolamine; metopimazine;trimethobenzamide; benzquinamine hydrochloride; and diphenidolhydrochloride.

As set forth previously, the nasal delivery systems that can be usedwith the present invention can take various forms including aqueoussolutions, non-aqueous solutions and combinations thereof. Aqueoussolutions include, for example, aqueous gels, aqueous suspensions,aqueous liposomal dispersions, aqueous emulsions, aqueous microemulsionsand combinations thereof. Non-aqueous solutions include, for example,non-aqueous gels, non-aqueous suspensions, non-aqueous liposomaldispersions, non-aqueous emulsions, non-aqueous microemulsions andcombinations thereof.

The various forms of the delivery system set forth above can include abuffer to maintain the pH of the dopamine receptor agonist, apharmaceutically acceptable thickening agent and a humectant. Desirably,the pH of the buffer is selected to maintain the dopamine receptoragonist in a non-ionized form. In particular, the pH of the buffer isselected to optimize the absorption of the dopamine receptor agonistacross the nasal mucosa. The particular pH of the buffer, of course, canvary depending upon the particular nasal delivery formulation as well asthe specific dopamine receptor agonist composition selected. Buffersthat are suitable for use in the present invention include acetate,citrate, prolamine, carbonate and phosphate buffers.

With respect to the non-aqueous formulations set forth above, suitableforms of buffering agents can be selected such that when the formulationis delivered into the nasal cavity of a mammal, selected pH ranges areachieved therein upon contact with, e.g., a nasal mucosa.

In the present invention, the pH of the compositions should bemaintained from about 3.0 to about 10.0. Compositions having a pH ofless than about 3.0 or greater than about 10.0 can increase the risk ofirritating the nasal mucosa of a recipient. Further, it is preferablethat the pH of the compositions be maintained from about 3.0 to about7.0.

The viscosity of the compositions of the present invention can bemaintained at a desired level using a pharmaceutically acceptablethickening agent. Thickening agents that can be used in accordance withthe present invention include methyl cellulose, xanthan gum,carboxymethyl cellulose, hydroxypropyl cellulose, carbomer, polyvinylalcohol, alginates, acacia, chitosans and combinations thereof. Theconcentration of the thickening agent will depend upon the agentselected and the viscosity desired. Such agents can also be used in apowder formulation discussed above.

The compositions of the present invention can also include a humectantto reduce or prevent drying of the mucus membrane and to preventirritation thereof Suitable humectants that can be used in the presentinvention include sorbitol, mineral oil, vegetable oil and glycerol;soothing agents; membrane conditioners; sweeteners; and combinationsthereof. The concentration of the humectant in the present compositionswill vary depending upon the agent selected.

In the present invention, other optional ingredients can also beincorporated into the nasal delivery system provided that they do notinterfere with the action of the dopamine receptor agonist orsignificantly decrease the absorption of the dopamine receptor agonistacross the nasal mucosa. Such ingredients include pharmaceuticallyacceptable excipients and preservatives.

To extend shelf life, preservatives can be added to the presentcompositions. Suitable preservatives that can be used with the presentcompositions include benzyl alcohol, parabens, thimerosal, chlorobutanoland benzalkonium chloride and preferably benzalkonium chloride is used.Typically, the preservative will be present in a composition in aconcentration of up to about 2% by weight. The exact concentration ofthe preservative, however, will vary depending upon the intended use andcan be easily ascertained by one skilled in the art.

The present invention provides for the compositions as described abovewhich are administered nasally to a mammal to treat erectiledysfunction. For purposes of the present invention, “administerednasally” or “nasal administration” is intended to mean that the dopaminereceptor agonists are combined with a suitable delivery system forabsorption across the nasal mucosa of a mammal, preferably, a human.

A preferred embodiment of the present invention provides for a nasallyadministered pharmaceutical composition that includes a therapeuticallyeffective amount of a dopamine receptor agonist dispersed in a buffer tomaintain the pH of the agonist, a pharmaceutically acceptable thickeningagent and a humectant. As used herein, “therapeutically effectiveamount” means a unit dosage of the present dopamine receptor agonistwhich is able to be combined with a pharmaceutically acceptable nasaldelivery system and absorbed through the nasal mucosa of a mammal toproduce an erection in about 1 hour, preferably in about 45 minutes,more preferably in about 30 minutes, and most preferably in 15 minutesor less which renders the intended physiological effect which is toinduce a penile erection in a mammal with penile erectile dysfunctionwithout causing substantial intolerable adverse side effects to themammal. Preferably, the dopamine receptor agonist is selected from agroup including apomorphine, chemically modified equivalents whichinclude a pro-drug and pharmaceutical salts thereof.

Another preferred embodiment of the present invention provides for amethod of treating impotence and male erectile dysfunction in a human inneed of such a treatment. This method includes administering into anasal cavity of a mammal for absorption through the nasal mucosa thereofa therapeutically effective dosage of a dopamine receptor agonist aspreviously set forth in combination with a nasal delivery system. Thedopamine receptor agonist is preferably selected from a group includingapomorphine, chemically modified equivalents which include a pro-drugand pharmaceutical salts thereof. For purposes of the present invention,the nasal delivery system can include a pharmaceutically acceptablebuffer, a thickening agent and a humectant.

In another preferred embodiment of the present invention, a method isprovided for administering a therapeutically effective amount of adopamine receptor agonist to a mammal through a nasal membrane withoutcausing substantial intolerable adverse side effects in the mammal. Thismethod includes delivering to a nasal membrane of a mammal a dopaminereceptor agonist which is dispersed in a nasal delivery system thatincludes a pharmaceutically acceptable buffer, a thickening agent and ahumectant. In this method, the dopamine receptor agonist is effectivefor the treatment of a sexual dysfunction in a mammal, particularlyimpotence and/or erectile dysfunction in a male mammal.

Another preferred embodiment of the present invention provides for anintranasal dosage unit for treating impotency in a mammal and which doesnot cause substantial intolerable adverse side effects in the mammal.The intranasal dosage unit includes an effective amount of a dopaminereceptor agonist in combination with a pharmaceutically acceptableintranasal carrier. This carrier includes a buffer. The pH of the bufferis selected as set forth above to facilitate dopamine receptor agonistabsorption through the nasal mucosa so an erection is achieved in about60 minutes, preferably in about 45 minutes, more preferably in about 30minutes and most preferably in 15 minutes or less after administration.

The following examples are provided to assist in further understandingthe invention. The particular materials and conditions employed areintended to be further illustrative of the invention and are notlimiting upon the reasonable scope thereof

A series of experiments were performed to illustrate features andadvantages of the present invention. Several conditions were common toeach experiment. For example, in Examples 1-4, apomorphine wasadministered to healthy male subjects who did not suffer from erectiledysfunction. Further, none of the subjects took any medication for twoweeks prior to these experiments.

The following examples show that apomorphine can be nasally administeredwithout causing substantial intolerable adverse effects. A differentdosage of apomorphine was administered in each experiment to determine apreferred range of dosages having minimal adverse effects.

EXAMPLE 1

TABLE 1 shows the results of an experiment in which 1.0 mg ofapomorphine HCL was nasally administered to nine male subjects.

TABLE 1 NUMBER OF SUBJECTS EXPERIENCING SYMPTOMS GIVEN BY THE DEGREESEVERITY OF THE SYMPTOM Mild to Mild, not moderate, Moderate, Severe,TOTAL troublesome, not Moderate, somewhat extremely NUMBER or of verytroublesome, somewhat severe, troublesome, OF SUBJECTS SYMPTOMS short ofshort troublesome, troublesome, or constantly EXPERIENCING EXPERIENCEDduration duration or persistent or persistent present SYMPTOMS NasalBurning 2 0 0 0 0 2 Sneezing 1 0 1 0 0 2 Unusual Taste 2 0 0 0 0 2Nausea 1 1 0 0 0 2 Tearing of Eyes 1 0 0 0 0 1 Lightheadedness 1 0 0 0 01 Tiredness 3 0 0 0 0 3 Congestion 1 0 0 0 0 1 Sweating 1 0 0 0 0 1

It should be noted that some of the subjects of this experiment sufferedfrom more than one symptom and one subject did not suffer from anysymptoms.

As shown in TABLE 1, the symptoms suffered by the subjects in thisexperiment were generally not troublesome and of very short duration.One subject, though, suffered from moderate sneezing and another subjectsuffered from mild to moderate nausea. The adverse effects with nasaladministration of 1.0 mg of apomorphine HCL were minimal and theseverity of the adverse effects were generally not troublesome.

EXAMPLE 2

TABLE 2 shows the results of an experiment in which 0.5 mg ofapomorphine HCL was nasally administered to three male subjects.

TABLE 2 NUMBER OF SUBJECTS EXPERIENCING SYMPTOMS GIVEN BY THE DEGREESEVERITY OF THE SYMPTOM Mild to Mild, not moderate, Moderate, Severe,TOTAL troublesome, not Moderate, somewhat extremely NUMBER or of verytroublesome, somewhat severe, troublesome, OF SUBJECTS SYMPTOMS short ofshort troublesome, troublesome, or constantly EXPERIENCING EXPERIENCEDduration duration or persistent or persistent present SYMPTOMS NasalBurning 2 0 0 0 0 2 Nasal Pain 1 0 0 0 0 1 Unusual Taste 1 0 0 0 0 1

One of the subjects of this experiment did not suffer any symptoms andtwo of the three subjects in this experiment suffered mild symptomswhich were not troublesome and were of very short duration. The resultsof this experiment show minimal adverse effects with nasaladministration of 0.5 mg of apomorphine HCL.

The results of this experiment also show that nasal administration ofapomorphine HCL was effective for inducing an erection. In particular,one of the three subjects experienced an erection while another felt thebeginning of an erection.

EXAMPLE 3

TABLE 3 shows the results of an experiment in which 2.0 mg ofapomorphine HCL was nasally administered to nine male subjects.

TABLE 3 NUMBER OF SUBJECTS EXPERIENCING SYMPTOMS GIVEN BY THE DEGREE OFSEVERITY OF THE SYMPTOM Mild to Mild, not moderate, Moderate, Severe,TOTAL troublesome, not Moderate, somewhat extremely NUMBER or of verytroublesome, somewhat severe, troublesome, OF SUBJECTS SYMPTOMS short ofshort troublesome, troublesome, or constantly EXPERIENCING EXPERIENCEDduration duration or persistent or persistent present SYMPTOMS NasalBurning 1 0 0 0 0 1 Sneezing 0 1 0 0 0 1 Unusual Taste 4 0 0 0 0 4Nausea 3 0 0 0 0 3 Lightheadedness 2 0 0 0 0 2

It should be noted that some of the subjects of this experiment sufferedfrom more than one symptom and one subject did not suffer from anysymptoms.

Eight of the nine subjects in this experiment suffered from symptoms ofmild degree as shown in TABLE 3. Further, the symptoms suffered by allof the subjects were not troublesome. The results of this experimentshow very minimal adverse effects with nasal administration of 2.0 mg ofapomorphine HCL.

The results of this experiment also show that nasal administration ofapomorphine HCL was effective for inducing an erection. In particular,three of the nine subjects of this experiment had a partial erectionwhile one subject felt an erection.

EXAMPLE 4

TABLE 4 shows the results of an experiment in which 4.0 mg ofapomorphine HCL was nasally administered to two male subjects.

TABLE 4 NUMBER OF SUBJECTS EXPERIENCING SYMPTOMS GIVEN BY THE DEGREESEVERITY OF THE SYMPTOM Mild to Mild, not moderate, Moderate, Severe,TOTAL troublesome, not Moderate, somewhat extremely NUMBER or of verytroublesome, somewhat severe, troublesome, OF SUBJECTS SYMPTOMS short ofshort troublesome, troublesome, or constantly EXPERIENCING EXPERIENCEDduration duration or persistent or persistent present SYMPTOMS Sneezing0 0 0 1 0 1 Nausea 0 1 0 0 0 1 Lightheadedness 0 1 0 0 0 1

One subject of this experiment did not suffer any symptoms while theother subject experienced mild to moderate nausea and lightheadedness,which were not troublesome and were of very short duration, and moderatesneezing, which was somewhat troublesome. In particular, this subjectfelt like vomiting, felt lightheaded for twenty minutes afterapomorphine was administered and sneezed four times. It is known in theart that the emetic effect of high dosages of apomorphine includesvomiting and therefore, it is believed that this subject suffered thesesymptoms due to the higher dosage of apomorphine.

The results of this experiment do not show substantial adverse effectswith nasal administration of 4.0 mg of apomorphine HCL.

Examples 1-4 show that apomorphine can be nasally administered atdifferent dosages without substantial adverse effects and further,adverse effects are minimal with a dosage of apomorphine of equal to orless than 2.0 mg.

EXAMPLE 5

TABLE 5 shows the solubility and stability of apomorphine hydrochloridedispersed in several different systems.

TABLE 5 System Solubility Solubility Improved # Composition of System pH(mg/mL) Enhancement % Stability* 1 Water 3.6 20.9 — — 2 Propylene Glycol— 84.5 304.3 Yes 3 Glycerin — 37.4 78.9 Yes 4 50% Propylene Glycol +50%Glycerin — 67.9 224.9 Yes 5 Polyethylene Glycol 400 — 19.9 None Yes 61.8% Ascorbic Acid + 2.3 25.0-30.0 19.6-43.5 Yes 98.2% Water 7 0.2%Sodium Ascorbate + 99.8% 5.0 20.0-25.0 0-19.6 Yes Water 8 0.5% SodiumMetabisulfite + 99.5% 3.1 249 19.1 Yes Water *Based on color change.

TABLE 5 shows the composition of several systems in which apomorphineHCL has been dispersed. System #1 includes water and served as a controlfor comparison with System #2-System #8. TABLE 5 also shows thesolubility of apomorphine HCL after it has been dispersed in the abovesystems. It also shows that the stability of apomorphine HCL has beenimproved after it has been dispersed in the above systems. The improvedstability of apomorphine HCL was determined based on the color change ofapomorphine HCL. For instance, a reduced degree of color formation afterdispersion of apomorphine HCL in a system would signify improvedstability.

As shown in TABLE 5, the solubility of apomorphine HCL clearly improvessignificantly when it is dispersed in the compositions of System#2-System #4. Further, the solubility of apomorphine HCL improvedmoderately when it was dispersed in the compositions of System #6-System#8.

Apomorphine HCL exhibited improved stability when dispersed in each ofSystem #2-System #8.

The results of this experiment demonstrate that a pharmaceuticalcomposition according to the present invention and including apomorphinedispersed in different systems as shown above, can improve thesolubility and stability of apomorphine.

Thus, while there have been described what are presently believed to bethe preferred embodiments of the present invention, those skilled in theart will realize that other and further embodiments can be made withoutdeparting from the spirit and scope of the invention, and it is intendedto include all such further modifications and changes as come within thetrue scope of the claims set forth herein.

What is claimed is:
 1. A pharmaceutical composition for treating sexualdysfunction in a mammalian subject consisting essentially of atherapeutically effective amount of apomorphine or pharmaceutical saltthereof formulated for intranasal administration in combination with aplurality of reducing agents yielding enhanced stability of saidapomorphine or pharmaceutical salt thereof wherein at least two of thereducing agents are selected from the group consisting of sodiummetabisulfite, ascorbic acid, and sodium ascorbate.
 2. Thepharmaceutical composition of claim 1, wherein at least one of saidplurality of reducing agents is sodium metabisulfite.
 3. Thepharmaceutical composition of claim 1, wherein at least one of saidplurality of reducing agents is sodium ascorbate.
 4. The pharmaceuticalcomposition of claim 1, wherein at least one of said plurality ofreducing agents is ascorbic acid.
 5. The pharmaceutical composition ofclaim 1, which is therapeutically effective following intranasaladministration to said subject to reduce symptoms of erectiledysfunction in the subject.
 6. The pharmaceutical composition of claim5, which is therapeutically effective to elicit an erection in saidsubject within about 30 minutes following intranasal administration. 7.The pharmaceutical composition of claim 1, wherein said composition isan aqueous solution.
 8. The pharmaceutical composition of claim 7,wherein said aqueous solution is selected from the group consisting ofaqueous gels, aqueous suspensions, aqueous liposomal dispersions,aqueous emulsions, aqueous microemulsions and combinations thereof. 9.The pharmaceutical composition of claim 1, wherein said composition is anon-aqueous solution.
 10. The pharmaceutical composition of claim 9,wherein said non-aqueous solution is selected from the group consistingof non-aqueous gels, non-aqueous suspensions, non-aqueous liposomaldispersions, non-aqueous emulsions, non-aqueous microemulsions andcombinations thereof.
 11. The pharmaceutical composition of claim 9,wherein said composition is a powder formulation.
 12. The pharmaceuticalcomposition of claim 11, wherein said powder formulation is selectedfrom the group consisting of simple powder mixtures, powdermicrospheres, coated powder microspheres, and combinations thereof.